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Notch signaling in the pathogenesis, progression and identification of potential targets for cholangiocarcinoma (Review)
- Authors:
- Published online on: January 19, 2022 https://doi.org/10.3892/mco.2022.2499
- Article Number: 66
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Copyright: © Vanaroj et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Cholangiocarcinoma (CCA) is a bile duct cancer with a high mortality rate. A significant proportion of the CCA cases and resultant mortalities worldwide are reported in the northeastern region of Thailand, where the major risk factor is infection by the liver fluke Opisthorchis viverrini through the consumption of improperly cooked cyprinoid fish that contain the parasite (1). There are currently no specific biomarkers for early detection of early-stage CCA, and patients are usually diagnosed when the disease has already progressed to the advanced stage, resulting in a poor prognosis. Liver resection is the standard therapy, but is not suitable for all cases. The 5-year survival rate following liver resection is <20%, depending on the aggressiveness, metastatic propensity and invasiveness of the tumors. Furthermore, CCA is resistant to chemotherapy and radiation (2). Investigation of the molecular mechanisms underlying the pathogenesis and progression of CCA has been an ongoing research focus, and several signaling molecules and pathways have been demonstrated to be involved in the pathogenesis and progression of CCA (3).
The Notch signaling pathway has been proposed as a conservative pathway that plays a key role in cell differentiation, proliferation and apoptosis (4). This signaling pathway is associated with several receptors and ligands. The four identified receptors are Notch1, Notch2, Notch3 and Notch4. The two families of ligands involved are the Delta-like family (DLL1, DLL3 and DLL4), and the Jagged family (Jagged1 and Jagged2). The activation of Notch signaling relies on two proteolytic enzymes in the a disintegrin and metalloprotease (ADAM) families and γ-secretase enzyme, which cleaves Notch receptors into two domains, i.e., Notch extracellular domain (NECD) and Notch intracellular domain (NICD). Following cleavage, NICD translocates to the nucleus and binds to transcription factors to promote expression of target genes, such as members of the hairy and enhancer of split (Hes) and Hes-related to YRPW motif (Hey) families (5).
Overexpression of Notch signaling genes is associated with the proliferation of certain cancers, including ovarian and breast cancers and glioma (6-8). However, overexpression of Notch signaling genes can also result in cancer cell apoptosis, such as in cases of liver cancer, small cell lung cancer and melanoma (9-11). The Notch signaling pathway in CCA cells is summarized in Fig. 1. The objectives of the present systematic review were to analyze the association of Notch signaling with the pathogenesis and progression of CCA, and uncover potential molecular targets for CCA control.
Materials and methods
The present systematic review was performed by combining the search results from three databases, i.e., PubMed, ScienceDirect and Scopus. The search terms applied were ‘cholangiocarcinoma’ AND ‘Notch signaling’. All articles were retrieved and downloaded to the EndNote X9 database (Thomson Reuters Company, Canada) for further analysis. They were initially screened by titles and abstracts to exclude irrelevant articles (those not involving CCA or the Notch signaling pathway). Full-text articles included after the initial screening were further evaluated by applying the predefined eligibility criteria. The inclusion criteria were as follows: i) Articles published between January 2004 and March 2020; ii) articles available as full-text articles in English; and iii) articles with in vitro/in vivo/ex vivo studies related to the Notch signaling pathway in CCA alone or CCA and hepatocellular carcinoma (HCC). The exclusion criteria were as follows: i) Articles related to other diseases or types of cancer; ii) articles related to pathways other than Notch signaling; iii) duplicated articles; or iv) review articles, letters to the editor, editorials, systematic analyses or meta-analyses.
Two reviewers extracted data independently and disparities were resolved by discussion and suggestions from the third reviewer. The information extracted for analysis included: First author's name and year of publication, objective(s) of the study, type of Notch receptor investigated, type of study (in vitro, in vivo and ex vivo), type of cell lines or animals used, laboratory techniques used, and key results and conclusions.
Results
A total of 89 articles from PubMed, ScienceDirect and Scopus databases were downloaded to the EndNote database. A total of 54 articles were excluded, and further analysis of the titles and abstracts of the remaining 36 articles led to the exclusion of 8 articles (5 articles unrelated to CCA, and 3 articles unrelated to the Notch signaling pathway in CCA). Finally, 27 articles were included in the analysis. The flow diagram of the study selection process is presented in Fig. 2, and the study summary is provided in Tables I and II. The associations of Notch1 and Notch2 signaling with CCA development and progression were investigated in 6 articles each, while those of Notch3 and Notch4 signaling were investigated in 3 and 1 article(s), respectively. The investigations involved in vitro (n=8), in vivo (n=12) and ex vivo (n=8) studies. The effects of modulators of Notch signaling as potential chemotherapeutic targets for CCA were investigated in 10, 5, 3 and 3 articles for Notch1, Notch2, Notch3 and Notch4 signaling pathways, respectively. The investigated modulators included cinobufagin, verteporfin-photodynamic therapy (PDT), γ-secretase inhibitor (GSI), γ-secretase inhibitor IX, endocannabinoids, corilagin, short hairpin (sh)RNA, and small-molecule inhibitors (SMIs) of aspartate-β-hydroxylase, anti-Notch1,2,3 and Jagged1, microRNA (miRNA)-34a, PIK3-catalytic subunit alpha (PIK3CA), PIK75, verteporfin, FLI-06, microfibrillar-associated protein 5 (MFAP5), ALW-II-41-27, ephrin A1, lymphotoxin β receptor (LTβR), xanthohumol and γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) (Table II).
Discussion
A summary of the currently available information on the association between Notch signaling and the pathogenesis and progression of CCA, including modulators (inhibitors or stimulators) of the signaling pathway as potential candidates for CCA chemotherapeutics, is presented in Fig. 3.
Upregulation of Notch signaling has been proposed as the mechanism associated with the transformation of mature hepatocytes into CCA cells (12-14). Nevertheless, activation of Notch signaling in hepatic progenitor cells, but not the transformation of hepatocytes, is proposed as the mechanism underlying CCA development (15). Increased expression of Notch1 has been linked to CCA development and progression (14,16-24). Notch1 has also been associated with cyclin E, the coordinate regulator protein in the G1 phase of the cell cycle; additionally, cyclin E can induce DNA damage (15). Increased NICD1 expression has also been associated with CCA development and progression through upregulation of cyclin E-associated DNA damage (15,25). Furthermore, Notch1 and Notch2 signaling have been reported to play a critical role in CCA formation (12-14,24,26-29), in which Jagged1 is the specific ligand. Upregulation of PIK3CA, AKT, and Jagged1 directly activates Notch 2 signaling and induces CCA development. Overexpression of Jagged1 enhances Notch2 signaling (26), while anti-Jagged1 treatment suppresses Notch2 signaling (27,28,30,31). At this time, the information on Notch3 and its role in CCA development and progression arelimited (24,32). Notch4 signaling has also been reported to promote the development of intrahepatic CCA (ICC) and is associated with a poor survival rate (24).
The activation of upstream Notch signaling molecules, including Yes-associated protein (YAP), AKT, mTOR, SNAIL and PIK3CA, are key processes that stimulate CCA formation through the transformation of mature hepatocytes into CCA cells (12). AKT is the main upstream Notch signaling molecule, which upregulates Notch1 and Notch2 (12-14,26,27,29,33). mTOR is another upstream activator of the Notch1 receptor (12,16). YAP is an upstream signaling molecule for both AKT and mTOR (12), and co-expression of YAP with AKT induces CCA development through activating Notch signaling via the Notch2 receptor and Jagged1 ligand (12,14,28,34), or with co-expression of NICD and shp53 (shRNA of p53) (35). Co-expression of AKT and Ras (the protein product of the oncogene KRAS2), on the other hand, induces tumorigenesis (21,27,29). MFAP5, enhanced green fluorescent protein-positive cells, mTOR and AKT, activate Notch signaling by increasing Notch1 expression, thereby enhancing CCA cell proliferation (12,16,17). Modulation of mutant genes, such as p53 (inactivation), isocitrate dehydrogenase1 (activation), or other pathways, such as the Wnt (β-catenin) pathway (activation), and the Myc pathway (activation) with co-expression of Notch signaling (activation) has been reported to induce CCA development (14,25,33,36). Upregulation of Notch1 expression may also be caused by additional factors, such as a high expression level of presenilin 1(37). Aspartate β-hydroxylase (ASPH) enhances activation of Notch signaling and stimulates CCA cell proliferation and migration. A high expression level of Notch1 can activate Ras-related C3 botulinum toxin substrate 1, which promotes CCA cell invasion and migration. ephrin type-A receptor 2 enhances the expression level of Notch1 and promotes CCA growth through the activation of AKT/RAS and by promoting lymphatic metastasis in ICC (21).
The role of Notch signaling in cancer pathogenesis and progression has also been demonstrated in several other types of cancer, including embryonal carcinoma (38), glioblastoma (39), melanoma (40), ependymoma (41), breast cancer (42), HCC (34), ovarian cancer (43), endometrial carcinoma (44), esophageal squamous cell carcinoma, gonadotroph pituitary adenomas (42), rhabdomyosarcoma (45), colon cancer (46), gastric cancer (47), gastrointestinal stromal tumors (48), anaplastic thyroid cancer (49), medullary thyroid cancer (50), pancreatic cancer (51), glioblastoma multiforme (52) and neuroendocrine neoplasms (53). The signaling molecules and pathways involved vary according to the type of cancer. Notch3, in addition to Notch1, appears to play an important role in breast cancer development and progression through its activation of cartilage oligomeric matrix protein expression (54).
Downregulation of Notch1 signaling by several interventions has been demonstrated to be a promising strategy for inhibition of CCA growth. These interventions include administration of cinobufagin (a traditional Chinese medicine extracted from parotid and skin glands of Chinese Toad) (21), xanthohumol (55), verteporfin-PDT (30), DAPT (23), PIK75 (PIK3CA-specific inhibitor), verteporfin, anti-Notch1 antibody (27), miRNA-34a (31) and small interfering (si)RNA LTβR (22). The downregulation of Notch1 siRNA expression reduces Notch1 levels, which results in inhibition of Notch signaling, suppression of cell proliferation, and promotion of apoptosis (20,22,27,30,31,55). Verteporfin-PDT downregulates the mRNA expression of Notch1, Notch2 and Jagged1(30); additionally, verteporfin can reduce YAP levels, decrease cell proliferation and induce apoptosis (14). Inhibition of MFAP5 using the γ-secretase inhibitor FLI-06 also suppressed Notch1 expression in CCA (20). Inhibition of Notch2 signaling using anti-Notch2 or anti-Jagged1 antibodies also suppressed Notch2 signaling (27) and miRNA-34a expression (31). Direct inhibition of Notch2 using miRNA-34a, PDT, anti-Notch2 or anti-Jagged1, and the Hippo pathway cascade decreases Notch2 levels, promotes apoptosis and inhibits cell proliferation. However, Notch1 and Notch2 signaling have been demonstrated to interact antagonistically with each other (27,36). Antagonists of Notch1 signaling can enhance Notch2 signaling, while Notch2 depletion can increase the levels of various components of the Notch1 signaling pathway, such as the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG), or anti-Notch1 and anti-Notch2 antibodies (27,34). AEA and 2-AG have been shown to exert different effects on Notch signaling. AEA, which has antiproliferative activity, upregulates Notch1 signaling via increasing the level of presenilin1, a catalytic subunit of γ-secretase. On the other hand, 2-AG, which has growth-promoting activity, upregulates Notch2 signaling via increasing the expression of presenilin 2, another catalytic subunit of γ-secretase. 2-AG activates Notch2 and enhances CCA cell proliferation (36). There have only been a limited number of studies related to Notch3 and its role in CCA, although is has been shown that using gene knockout or shRNA and SMIs to decrease Notch3 levels suppresses CCA growth (32). Both shRNA and SMIs inhibit ASPH and Notch signaling to suppress CCA cell proliferation and migration (56).
The potential of the aforementioned interventions for the control of other types of cancer has also been demonstrated. These include cinobufagin for osteosarcoma (57), xanthohumol for hepatocarcinoma (58), FLI-06 for tongue cancer (59), GSI for glioblastoma cancer stem cells (60), T-cell for acute lymphoblastic leukemia (61), osteosarcoma (62) and triple-negative breast cancer (63), and DAPT for glioma (64), colorectal cancer (65), cervical cancer (66), gastric cancer (67), head/neck squamous cell carcinoma (68), osteosarcoma (69), choriocarcinoma (70) and ovarian cancer (71). In addition, miRNA-34a has also been reported to inhibit the progression of pancreatic cancer and medulloblastoma (72,73), and siRNA interference has been reported to inhibit cell proliferation in glioblastoma multiforme (74).
In summary, overexpression/upregulation of the expression of Notch ligands (e.g., Jagged1) and Notch receptors (Notch1, Notch2, Notch3 and Notch4), as well as upregulation of the expression of upstream Notch signaling molecules, promotes CCA development and progression. Therefore, downregulation of Notch1 signaling through several interventions is a promising strategy for inhibition of CCA development and progression. However, further studies focusing on the application of these modulators of Notch signaling in a clinical setting must be performed in the future.
Acknowledgements
The authors thank Mr. Ethan Vindvamara (American molecular biologist; Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand) for English editing of the manuscript.
Funding
Funding: The study was supported by the Research Team Promotion Grant, National Research Council of Thailand (grant no. NRCT 820/2563), Thammasat University (Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma) and Thammasat University Research Fund (contract no. TUFT 65/2564).
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study.
Authors' contributions
PV, WC and KN conceived the study and analyzed and interpreted the data. PN performed the background research, collected the data and wrote the manuscript. WC and KN critically revised the manuscript for important intellectual content. Data authentication is not applicable. All the authors have read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
All the authors declare that they have no competing interests.
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